DESCRIPTION: (Applicant's Abstract) Cholinergic projections are present throughout the brain, and nicotinic receptors (nAChRs) modulate multiple neurotransmitter systems. Because of these properties, nicotinic mechanisms modulate neuronal activity in broad areas of the brain. These abilities are best exemplified by the recent finding that two different single amino acid mutations in a nAChR produce epilepsy. Further support arises from a wide range of evidence suggesting that the alpha7 nAChR subunit is linked to sensory gating deficits, as observed in schizophrenic patients. Guided by these findings, our working hypothesis is that nicotinic systems modulate circuit excitability and, consequently, influence observable and testable responses. We will study nicotinic modulation of neuronal excitability with brain slices and invivo recordings from the hippocampus. Our long-standing investigations into new nicotinic synaptic mechanisms will continue, and we will examine the influence of nAChR-mediated calcium signals in common forms of hippocampal synaptic plasticity. From the same areas of the brain, we will examine circuit activity using invivo recordings from multielectrode assemblies that can isolate the firing of many individual neurons and simultaneously provide detailed multiple EEG records. The study of synaptic mechanisms and invivo recordings will provide different levels of information about the neuronal activity of the hippocampus. Because the invivo recordings are made in wake, freely moving rats or mice, we can examine neuronal activity arising from experimental tests or behavioral tasks. Cholinergic activity influences the sleep/wake cycle, spatial tasks, and sensory gating, as quantified by models of acoustic startle, but the nicotinic contributions have not been studied with combined slice physiology and multi-unit invivo recordings. Because alpha7 and beta2 are the most common nAChRs in the hippocampus, we will determine nicotinic contributions by comparing wild-type, alpha7-null, heterozygous alpha7L250T-mutant, and beta2-null mice. We have all these mice backcrossed for six generations.